KT1, a novel NK trispecific antibody for the treatment of AML and MDS
John DiPersio
MD, PhDWashington University in St. Louis
Project Term: July 1, 2024 - June 30, 2027
New treatments for AML and MDS are urgently needed. We have developed and performed preliminary testing of a novel, patent-protected, trispecific NK cell engager named KT1 which targets AML blasts and leukemia stem cells (LSCs) expressing CD33 and CD123 for elimination by effector cells that express CD16a/b. We plan to test the ability of KT1 to release cytokines and facilitate killing of CD33- and/or CD123-expressing targets by different types of CD16a/b-positive effector cell populations including resting natural killer (NK) cells, cytokine-induced memory-like (ML) NK cells, gamma/delta T cells, and macrophages both in vitro and in leukemic mice. We anticipate that a future treatment of AML and/or MDS with KT1 combined with a donor leukocyte transfer of allogeneic NK, ML NK, or gamma/delta T cells will have excellent therapeutic efficacy and a far better safety profile than many currently studied immunotherapies being tested in patients with AML or MDS.
AML is a devastating disease, more difficult to treat than most hematologic malignancies. Many patients reach a first remission after induction chemotherapy but rapidly become victims of relapsed disease. Our team has designed a therapeutic molecule, KT1, specifically conceived to treat relapsed or refractory AML. The molecule has new functional capabilities uniquely enabled by its patent-protected molecular format of a "tri-specific, dual-targeting triplebody". A single triplebody molecule can bind one copy each of 2 different tumor markers on the surface of the same AML cell. This new binding mode (called "dual-targeting") enables a new functional capability: a preferential binding to target cells carrying both markers in greater density on their cell surface than target cells carrying both in low combined surface density. We have identified a suited pair of surface markers named CD33 and CD123 that are expressed in greater density on the surface of AML blasts than most of the patients' non-malignant cells. In addition to binding CD33 and CD123 on AML cells, KT1 has a binding site for a molecule named CD16 that is expressed on normal natural killer (NK) cells, gamma/delta T (gd T) cells and macrophages that are present in the patient. Upon treatment with KT-1, the normal NK, gd T, and macrophages can kill the patients AML cells. Our team recently found that we can significantly improve the ability of normal NK cells to kill AML cells by treating them overnight in the lab with three molecules named “cytokines” to make memory-like (ML) NK cell. These ML NK cells are very safe in humans and kill AML cells better than conventional NK (cNK) cells upon engagement of CD16 on their surface by a molecule such as KT1.
In this proposal, we will evaluate KT1's ability to kill AML cells in the laboratory (Aim 1) and in mice (Aim 2) after treatment with cNK, ML NK, gd T and macrophage effector cells. We will also use “humanized” mice that have a human blood system and AML to check the specificity, safety, and efficacy of KT-1 in the presence of normal human blood cells (Aim 3). These types of studies are mandated by regulatory authorities like the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) before we can test KT1 in humans.
We anticipate that a future clinical treatment of AML and MDS patients with KT1, combined with a transfer of donor ML NK cells, has the potential to become an efficient therapy, better tolerated and with a better safety profile than currently available treatments.